Pivotal Study to Evaluate Efficacy and Safety of SP5M002 Inj. as Compared to Synovian Inj. in Patients With Mild to Moderate Knee Osteoarthritis

A Multi-center, Randomized, Double-Blinded, Active Controlled, Phase III Study to Evaluate Efficacy and Safety of SP5M002 Injection Compared With Synovian Injection in Patients With Mild to Moderate Knee Osteoarthritis

This is a randomized, double-blind, multicenter, Active Controlled, pivotal clinical trial to assess the efficacy and safety of the novel hexamethylenediamine (HMDA) cross-linked hyaluronate intra-articular injection (SP5M002) compared with an active comparator, the 1,4-butanediol diglycidyl ether (BDDE) cross-linked hyaluronate (Synovian) in patients with knee osteoarthritis.

Study Overview

• Status: Active, not recruiting
• Conditions: Osteoarthritis
• Intervention / Treatment: Device: SP5M002 inj; Device: Synovian inj

• Study Type: Interventional
• Enrollment (Actual): 297
• Phase: Phase 3

Contacts and Locations

Study Locations

• Korea, Republic of
  • Daegu, Korea, Republic of
    • Kyungpook National University Hospital
  • Daegu, Korea, Republic of
    • Yeungnam University Medical Center
  • Gwangju, Korea, Republic of
    • Chonnam National University Bitgoeul Hospital
  • Incheon, Korea, Republic of
    • Gachon University Gil Medical Center
  • Jeonju, Korea, Republic of
    • Jeonbuk National University Hospital
  • Jinju, Korea, Republic of
    • Gyeongsang National University Hospital
  • Sejong, Korea, Republic of
    • Chungnam National University Hospital
  • Seongnam, Korea, Republic of
    • CHA University Bundang Medical Center
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Ewha Womans University Mokdong Hospital
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Kyung Hee University Hospital at Gangdong
  • Seoul, Korea, Republic of
    • The Catholic University of Korea, Seoul St. Mary's Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Boramae Medical Center
  • Seoul, Korea, Republic of
    • KyungHee University Hospital
  • Seoul, Korea, Republic of
    • Gangnam Severance Hospita

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult males and females aged 40 years or older as of the date of written consent
2. Subject with knee osteoarthritis whose X-ray test results within 6 months from the screening or at the screening visit correspond to grades I - III of the Kellgren & Lawrence scale

3. Subject diagnosed with unilateral or bilateral knee osteoarthritis according to the clinical diagnostic criteria of the American College of Rheumatology (ACR) at screening who have knee joint pain and meet three or more of the following conditions

   • Over 50 years of age

     • Less than 30 minutes of morning stiffness ③ Crepitus on active motion ④ Bony tenderness ⑤ Bony enlargement ⑥ No palpable warmth of synovium
4. Weight bearing pain (WBP) of at least one of both knee joints on 100 mm-VAS ≥ 40 mm when measured at screening and baseline [However, if both sides have symptoms, the knee joint with the higher WBP becomes the joint for evaluation, and the selected joint cannot be changed during the study period.]
5. Walk without relying on a walking aid such as a walker or cane (patients who have been using a walking aid every day since 6 months prior to the screening visit can use the walking aid, and must use the walking aid in the same way throughout the study period.)
6. Ability to fully understand and complete the safety and efficacy measurement questionnaire
7. Voluntary decision for participation and provision of written consent to comply with the precautions after hearing and fully understanding the detailed explanation of the purpose, method, and effects of this study

Exclusion Criteria:

1. Body mass index (BMI) ≥ 35 kg/m2 at screening
2. Hip osteoarthritis or osteoarthritis of another joint that is severe enough to preclude evaluation of knee osteoarthritis at the time of screening

3. Having the following diseases that may affect the efficacy and safety evaluation but not being limited to the following

   • Septic arthritis, rheumatoid arthritis, gout, recurrent pseudogout arthritis, trauma that may damage joint cartilage, congenital abnormalities, calcium deposition disease, diabetes, ochronosis, hemochromatosis, acromegaly, Wilson's disease, primary osteochondrosis, genetic diseases (e.g., hyperkinesis), secondary osteoarthritis caused by collagen gene abnormalities, etc.
   • Sudek's atrophy or severe painful diseases such as Paget's disease
4. Infection or skin disease in the joint area that is unsuitable for injection at the time of screening
5. Active or suspected knee joint infection at the time of screening
6. Complete loss of the Patello-femoral joint space

7. Received the following treatments within 14 days of the screening visit (except those who have passed a 14-day wash-out) or scheduled to be administered during the study period

   • Taking medicines containing ingredients such as glucosamine, chondroitin sulfate, and diacerhein
   • Taking herbal medicines and herbal medicines for osteoarthritis
   • Taking anti-inflammatory painkillers, non-steroidal anti-inflammatory drugs (NSAIDs, prescription/non-prescription drugs), etc. (administration of acetaminophen allowed if passing a 3 day wash-out)
   • Taking oral steroids
   • Hospital physical therapy or oriental medicine treatment (cupping, acupuncture, moxibustion, etc.)
8. Intra-articular injection, such as intra-articular corticosteroid, at the injection site within 6 months from the time of screening
9. Systemic use of steroids within 3 months from the time of screening (including inhalants, however, topical application is permitted only on the upper body)
10. Surgical operations such as knee joint replacement, including arthroscopic surgery, at the administration site within 6 months from the time of screening; or expecting surgery within 6 months
11. Moderate or severe joint effusion by Patella tap test at the screening visit
12. History of hypersensitivity to ingredients of the IP or active control drug
13. Antiplatelet agents (excluding aspirin of 300 mg/day or less), heparin, oral anticoagulants (coumarin anticoagulants, thrombin inhibitors, Factor Xa inhibitors, etc.), and thrombolytics must be used during the study
14. Clinically significant abnormalities in liver function (3 times or more than the upper limit of normal for ALT/AST) or abnormalities in renal function (3 times or more than the upper limit of normal for serum creatinine), or severe liver or renal disease at the discretion of the investigator which is judged to have an impact on the effectiveness and safety evaluation of the study

15. The following clinically significant diseases in the past or present

    • Diagnosis of malignancy within 5 years prior to screening or currently
    • Cardiac disorders (myocardial infarction, coronary artery bypass surgery, arrhythmia, and other serious Cardiac disorders, etc.)
    • Uncontrolled hypertension (systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg)
    • Severe endocrine diseases (diabetes insipidus, Cushing's disease, etc.) which is judged to have an impact on the efficacy and safety evaluation of the study
16. Currently pregnant or lactating; or planning to become pregnant/lactating during this study
17. Women of childbearing age who have not undergone sterilization surgery, women less than 1 year after menopause, or men who do not agree to avoid pregnancy or use appropriate contraceptive methods during the study period
18. Planned to participate in another study during the study period or having administered (applied) other investigational product (investigational device) within 3 months prior to the screening visit
19. Difficult to conduct the study as judged by the investigator due to other reasons

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Synovian inj; Synovian inj 3 ml pre-filled syringe into Knee joint cavity of osteoarthritis patients	Device: Synovian inj; pre-filled syringe
Experimental: SP5M002 inj; SP5M002 inj 3 ml pre-filled syringe into Knee joint cavity of osteoarthritis patients	Device: SP5M002 inj; pre-filled syringe

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in [Weight-Bearing Pain (WBP)-100mm-visual analogue scale (VAS)] at Week 12 from baseline (visit 2)	* Weight Bearing Pain (WBP) - 100mm-visual analogue scale (VAS)	12 weeks
Change in [Weight-Bearing Pain (WBP)-100mm-visual analogue scale (VAS)] at Week 6 from baseline (visit 2)	* Weight Bearing Pain (WBP) - 100mm-visual analogue scale (VAS)	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the following at each visit: Weight Bearing pain (WBP) (Weeks 2, 24, and 36) from baseline (Visit 2)	Outcome Measurement of Weight Bearing pain(WBP): 100mm-visual analogue scale (VAS)	week 2, 24, 36
Changes in the following at each visit: Rest pain (RP) (Weeks 2, 6, 12, 24, and 36) from baseline (Visit 2)	Outcome Measurement of Rest pain (RP): 100mm-visual analogue scale (VAS)	week 2,6,12, 24, 36
Changes in the following at each visit: Night pain (NP) (Weeks 2, 6, 12, 24, and 36) from baseline (Visit 2)	Outcome Measurement of Night pain (NP): 100mm-visual analogue scale (VAS)	week 2,6,12, 24, 36
Changes in the following at each visit: Motion pain (MP) (Weeks 2, 6, 12, 24, and 36) from baseline (Visit 2)	Outcome Measurement of Motion pain (MP): 100mm-visual analogue scale (VAS)	week 2,6,12, 24, 36
Changes in the following at each visit: Patient Global Assessment(PGA) (Weeks 2, 6, 12, 24, and 36) from baseline (Visit 2)	Outcome Measurement of Patient Global Assessment(PGA): 100mm-visual analogue scale (VAS)	week 2,6,12, 24, 36
Changes in the following at each visit: Investigator Global Assessment (IGA) (Weeks 2, 6, 12, 24, and 36) from baseline (Visit 2)	Outcome Measurement of Investigator Global Assessment (IGA) : 100mm-visual analogue scale (VAS)	week 2,6,12, 24, 36
Changes in the following at each visit: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score and individual score evaluation (Pain, function, stiffness) (Weeks 2, 6, 12, 24, and 36) from baseline (Visit 2)	Outcome Measurement of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score and individual score evaluation (Pain, function, stiffness) : WOMAC-Likert Assessment (5-point Likert scale)	week 2,6,12, 24, 36
Physical assessments at each post-administration visit: Swelling (Weeks 2, 6, 12, 24, and 36)	Outcome Measurement of Swelling : 4-point scale *4-point scale: 0(none)/1(mild)/2(moderate)/3(severe)	week 2,6,12, 24, 36
Physical assessments at each post-administration visit: joint-line tenderness on pressure (Weeks 2, 6, 12, 24, and 36)	Outcome Measurement of joint-line tenderness on pressure : 4-point scale *4-point scale: 0(none)/1(mild)/2(moderate)/3(severe)	week 2,6,12, 24, 36
Physical assessments at each post-administration visit: range of motion (Weeks 2, 6, 12, 24, and 36)	The angle was recorded as is for the range of motion.	week 2,6,12, 24, 36
Proportion (%) of participants who took rescue medication at each post-administration visit and dose of rescue medication (Weeks 2, 6, 12, 24, and 36)		week 2,6,12, 24, 36
Post-administration response rate A. Proportion at which WBP decreases by at least 20 mm or improves by at least 40% from baseline at the time of evaluation (B section-Description)	*B. Response rate of OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) I. At least 50% improvement in WOMAC pain or function at the time of evaluation; or at least a 20 point improvement from baseline; or II. meeting 2 of the 3 conditions below At least 20% improvement in WOMAC pain, at least a 10 point improvement from each baseline At least 20% improvement in WOMAC function, at least a 10 point improvement from each baseline At least 20% improvement in patient's global assessment (100 mm-VAS) and at least a 10 point improvement from each baseline	week 2,6,12, 24, 36

Other Outcome Measures

Outcome Measure	Time Frame
The incidence rate of Pre-treatment AEs	From Week 0 to week 24
The incidence rate of Solicited Local AEs	From Week 0 to week 24
The incidence rate of treatment-emergent adverse event (TEAE)	From Week 0 to week 24
The incidence rate of Serious TEAEs	From Week 0 to week 24
The incidence rate of Serious TEAEs leading to Drug withdrawn	From Week 0 to week 24
The incidence rate of Serious TEAEs leading to Death	From Week 0 to week 24
The incidence rate of abnormal CS at Post-Treatment on Laboratory	From Week 0 to week 24
The incidence rate of abnormal CS at Post-Treatment on Electrocardiogram	From Week 0 to week 24
The incidence rate of abnormal on Physical Examination	From Week 0 to week 24

Collaborators and Investigators

• Sponsor: Shin Poong Pharmaceutical Co. Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2023
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: April 30, 2024
• First Submitted That Met QC Criteria: April 30, 2024
• First Posted (Actual): May 3, 2024

Study Record Updates

• Last Update Posted (Actual): May 3, 2024
• Last Update Submitted That Met QC Criteria: April 30, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Knee osteoarthritis, Intra-articular injection, hexamethylenediamine(HMDA), Cross-linked hyaluronate
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: SP-HA-003-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No